Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1
Macrophage foam cell is the predominant cell type in atherosclerotic lesions. Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid ef...
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| Veröffentlicht in: | The Journal of biological chemistry 2011-02, Vol.286 (5), p.3370-3378 |
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| creator | Ma, Loretta Dong, Fumin Denis, Maxime Feng, Ying Wang, Ming-Dong Zha, Xiaohui |
| description | Macrophage foam cell is the predominant cell type in atherosclerotic lesions. Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid efflux, and ATP-binding cassette transporter A1 (ABCA1) greatly facilitates this process. Remarkably, we found that st-Ht31 completely reverses foam cell formation, and this process is ABCA1-dependent. The reversal is also accompanied by the restoration of well modulated inflammatory response to LPS. There is no detectable toxicity associated with st-Ht31, even when cells export up to 20% cellular cholesterol per hour. Using FRET-based PKA biosensors in live cells, we provide evidence that st-Ht31 drives cholesterol efflux by elevating PKA activity specifically in the cytoplasm. Furthermore, ABCA1 facilitates st-Ht31 uptake. This allows st-Ht31 to effectively remove cholesterol from ABCA1-expressing cells. We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages. |
| doi_str_mv | 10.1074/jbc.M110.173666 |
| format | Article |
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Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid efflux, and ATP-binding cassette transporter A1 (ABCA1) greatly facilitates this process. Remarkably, we found that st-Ht31 completely reverses foam cell formation, and this process is ABCA1-dependent. The reversal is also accompanied by the restoration of well modulated inflammatory response to LPS. There is no detectable toxicity associated with st-Ht31, even when cells export up to 20% cellular cholesterol per hour. Using FRET-based PKA biosensors in live cells, we provide evidence that st-Ht31 drives cholesterol efflux by elevating PKA activity specifically in the cytoplasm. Furthermore, ABCA1 facilitates st-Ht31 uptake. This allows st-Ht31 to effectively remove cholesterol from ABCA1-expressing cells. We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.173666</identifier><identifier>PMID: 21106522</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>A-Kinase Anchoring Protein ; ABC Transporter ; ABCA1 ; ABCA1 protein ; Animals ; Arteriosclerosis ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters - physiology ; ATP-binding protein ; Biological Transport - drug effects ; Biosensors ; Cell Line ; Cholesterol ; Cholesterol - metabolism ; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors ; Cytoplasm ; fluorescence resonance energy transfer ; Fluorescence Resonance Energy Transfer (FRET) ; Foam Cells - cytology ; Foam Cells - drug effects ; Inflammation ; Lipids ; Lipopolysaccharides ; Macrophage ; Macrophages ; Macrophages - cytology ; Mice ; Phospholipids ; Protein kinase A ; Protein Kinase A (PKA) ; Proteins - pharmacology ; Toxicity</subject><ispartof>The Journal of biological chemistry, 2011-02, Vol.286 (5), p.3370-3378</ispartof><rights>2011 © 2011 ASBMB. 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We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.</description><subject>A-Kinase Anchoring Protein</subject><subject>ABC Transporter</subject><subject>ABCA1</subject><subject>ABCA1 protein</subject><subject>Animals</subject><subject>Arteriosclerosis</subject><subject>ATP Binding Cassette Transporter 1</subject><subject>ATP-Binding Cassette Transporters - physiology</subject><subject>ATP-binding protein</subject><subject>Biological Transport - drug effects</subject><subject>Biosensors</subject><subject>Cell Line</subject><subject>Cholesterol</subject><subject>Cholesterol - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</subject><subject>Cytoplasm</subject><subject>fluorescence resonance energy transfer</subject><subject>Fluorescence Resonance Energy Transfer (FRET)</subject><subject>Foam Cells - cytology</subject><subject>Foam Cells - drug effects</subject><subject>Inflammation</subject><subject>Lipids</subject><subject>Lipopolysaccharides</subject><subject>Macrophage</subject><subject>Macrophages</subject><subject>Macrophages - cytology</subject><subject>Mice</subject><subject>Phospholipids</subject><subject>Protein kinase A</subject><subject>Protein Kinase A (PKA)</subject><subject>Proteins - pharmacology</subject><subject>Toxicity</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUk1v1DAQjRCILoUzN_CNS9P6I3aSC1IUtbSiFVVZJG6W40w2rrL2Yjsr-EX8TRxtqeCAsA8ey2_ezDy_LHtN8CnBZXF23-nTG7LcSiaEeJKtCK5Yzjj5-jRbYUxJXlNeHWUvQrjHaRU1eZ4d0ZQiOKWr7OdlZOQEKXTrXQRj0UdjVQDUoMbq0XljN-jKjqYz0fmTFPazhoDuXDeHiNrRTRAieDeh82GY5u9I2R7dwR58SLAbpb3bjWoD6MKpLWphmlLktyoaZ1EcvZs3I2rWt3lnbL8Ua1UIECOgtVc27JxP7KghL7Nng5oCvHo4j7P1xfm6vcyvP324apvrXHNRxLyngg9YqYJ0XY2J6mjPS6qxwEVZ1IwOValpyapKU6606HXVdYIzUQsmWFmw4-z9gXY3d1voNdjo1SR33myV_yGdMvLvF2tGuXF7yXDaBUsE7x4IvPs2J23k1gSdxlYW3BxkjUvCKebiv8iqqERV1nhp6uyATGKG4GF47IdgudhAJhvIxQbyYIOU8ebPMR7xv_89Ad4eAINyUm28CfLLZ4oJw6RmnNOFoj4gIKm9N-Bl0Aasht540FH2zvyz_C9Mncvm</recordid><startdate>20110204</startdate><enddate>20110204</enddate><creator>Ma, Loretta</creator><creator>Dong, Fumin</creator><creator>Denis, Maxime</creator><creator>Feng, Ying</creator><creator>Wang, Ming-Dong</creator><creator>Zha, Xiaohui</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20110204</creationdate><title>Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1</title><author>Ma, Loretta ; Dong, Fumin ; Denis, Maxime ; Feng, Ying ; Wang, Ming-Dong ; Zha, Xiaohui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-d265f0aa41bb901ab2d572c060474932f87c27388c25ac6dc8bb653696363743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>A-Kinase Anchoring Protein</topic><topic>ABC Transporter</topic><topic>ABCA1</topic><topic>ABCA1 protein</topic><topic>Animals</topic><topic>Arteriosclerosis</topic><topic>ATP Binding Cassette Transporter 1</topic><topic>ATP-Binding Cassette Transporters - physiology</topic><topic>ATP-binding protein</topic><topic>Biological Transport - drug effects</topic><topic>Biosensors</topic><topic>Cell Line</topic><topic>Cholesterol</topic><topic>Cholesterol - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</topic><topic>Cytoplasm</topic><topic>fluorescence resonance energy transfer</topic><topic>Fluorescence Resonance Energy Transfer (FRET)</topic><topic>Foam Cells - cytology</topic><topic>Foam Cells - drug effects</topic><topic>Inflammation</topic><topic>Lipids</topic><topic>Lipopolysaccharides</topic><topic>Macrophage</topic><topic>Macrophages</topic><topic>Macrophages - cytology</topic><topic>Mice</topic><topic>Phospholipids</topic><topic>Protein kinase A</topic><topic>Protein Kinase A (PKA)</topic><topic>Proteins - pharmacology</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Loretta</creatorcontrib><creatorcontrib>Dong, Fumin</creatorcontrib><creatorcontrib>Denis, Maxime</creatorcontrib><creatorcontrib>Feng, Ying</creatorcontrib><creatorcontrib>Wang, Ming-Dong</creatorcontrib><creatorcontrib>Zha, Xiaohui</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Loretta</au><au>Dong, Fumin</au><au>Denis, Maxime</au><au>Feng, Ying</au><au>Wang, Ming-Dong</au><au>Zha, Xiaohui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-02-04</date><risdate>2011</risdate><volume>286</volume><issue>5</issue><spage>3370</spage><epage>3378</epage><pages>3370-3378</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Macrophage foam cell is the predominant cell type in atherosclerotic lesions. 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We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21106522</pmid><doi>10.1074/jbc.M110.173666</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2011-02, Vol.286 (5), p.3370-3378 |
| issn | 0021-9258 1083-351X |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | A-Kinase Anchoring Protein ABC Transporter ABCA1 ABCA1 protein Animals Arteriosclerosis ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters - physiology ATP-binding protein Biological Transport - drug effects Biosensors Cell Line Cholesterol Cholesterol - metabolism Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors Cytoplasm fluorescence resonance energy transfer Fluorescence Resonance Energy Transfer (FRET) Foam Cells - cytology Foam Cells - drug effects Inflammation Lipids Lipopolysaccharides Macrophage Macrophages Macrophages - cytology Mice Phospholipids Protein kinase A Protein Kinase A (PKA) Proteins - pharmacology Toxicity |
| title | Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1 |
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